Relapse remains the most important cause of failure for many patients undergoing either autologous or allogeneic transplant for the treatment of malignant lymphoma and acute myelogenous leukemia. This project will focus on studies of radioimmunotherapy targeted to tumor-associated antigens, as a component of the preparatory regimens for autologous and allogeneic hematopoietic cell transplantation used in the treatment of these diseases. The proposed studies seek to improve the anti-tumor efficacy, as well as reduce the toxicity of the procedure which will extend the application of hematopoietic cell transplantation (HCT) to older patients who form the majority of patients with both AML and lymphoma. The proposed studies will investigate the incorporation of radiolabeled antibodies conjugated to a heavy metal radioisotope (Yttrium-90) that target either the CD20 antigen on malignant B-cells or the CD33 antigen on blasts in patients with AML and myelodysplasia. We propose to perform five clinical studies using novel regimens for autologous or allogeneic transplant for AML and B-cell lymphoma: 1) For patients with advanced lymphoma (low-grade, intermediate-grade, and mantle cell) we will continue our studies of high-dose 90Y-labeled anti-CD20 antibody combined with etoposide and cyclophosphamide in the Phase II setting;2) For older patients (age>60) with relapsed lymphoma we will extend our Phase I observations to a Phase II study of 90Y-labeled anti-CD20 antibody combined with BEAM chemotherapy in order to develop an effective regimen that can be used safely in this population of patients; 3) 90Y-labeled anti-CD20 antibody will also be developed as part of a reduced intensity allogeneic transplant regimen for patients with lymphoma who are not candidates for an autologous approach, including those with relapsed mantle cell lymphoma, multiple relapsed low-grade lymphoma, or patients who have relapsed after autologous transplant;4) For patients with AML, who have intermediate- and high-risk cytogenetics, we will initiate a study of 90Y-labeled anti-CD33 antibody to replace total body irradiation in combination with etoposide and cyclophosphamide for autologous transplant;5) After completion of a Phase I safety study, we will conduct a Phase II study with this regimen. For patients with advanced leukemia (early relapse, older age, AML with prior MDS, relapse after auto-transplant), we will incorporate the 90Y-labeled anti-CD33 antibody into a reduced intensity allogeneic transplant regimen to improve the outcome for this high-risk population of patients. It is the general hypothesis of this project that targeted radiation therapy as a component of the autologous and allogeneic transplant preparative regimens will help improve therapeutic efficacy by decreasing post-HCT disease relapse and by reducing toxicity, thereby extending the potential benefit of treatment to a larger population of patients with these diseases.